Abstract Alzheimer's Disease (AD) is a severe disease affecting many people and ~90% are sporadic. Alcohol damages liver, pancreas, heart, brain, and muscle. Alcohol abuse results in cognitive impairment and dementia. Extensive clinical studies also strongly support a link between alcohol use disorders with AD and AD-related dementias (ADRD) but mechanisms are poorly understood. Our lab focuses on the biology of autophagy, a conserved lysosomal degradation pathway that regulates organelle and protein homeostasis. Impaired autophagy occurs in various human diseases including alcoholic liver disease (ALD) and AD. Autophagy generally declines with age, which promotes an accumulation of misfolded proteins including tau and ? amyloid as well as damaged mitochondria. Our parent grant (R01 AA020518) studies the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in alcohol-induced liver injury. We have established that alcohol induces dysfunction of TFEB, impairs lysosomal biogenesis and mitophagy, and increases the extent of ubiquitinated protein aggregates in mouse hepatocytes. Given ALD and AD share common pathologies such as accumulation of protein aggregates and mitochondrial dysfunction, we speculate ALD and AD may share common underlying functional deficits. To further explore this possibility, we evaluated hippocampi from our alcohol-treated mice, and found chronic-plus-binge alcohol markedly decreased TFEB levels and increased protein ubiquitination. Indeed, we found that TFEB levels decline in liver during natural aging. These collective observations suggest alcohol consumption and aging may synergistically interact to perturb the TFEB-lysosome biogenesis axis, thereby leading to impaired brain autophagy. Impaired autophagy is a well-recognized component of AD, and we expect extending our TFEB studies to the brain will provide insight into age-related declines in autophagy-lysosome biology that become more profound in the setting of AD and alcohol abuse. Here, we hypothesize chronic alcohol consumption compounds age-related TFEB- mediated lysosomal biogenesis in the brain, which in turn leads to an accumulation of damaged mitochondria and protein aggregates. Our proposed experiments promise to establish links between brain aging, alcohol consumption, and AD pathology. We further predict overexpression of TFEB and constitutively active TFEB knockin in mice will protect against these brain aging and alcohol-induced pathologies. We will also assess the brain-effects of novel TFEB agonists identified from a high-throughput screening during our parent R01 studies. The work proposed here represents a natural extension of our ongoing liver research to the brain. Work performed under this supplement will enrich the AD and brain aging fields about the potential role of TFEB in autophagy and lysosome biology, which has further implications on the origin and role of mitochondrial dysfunction in AD and brain aging. The experiments we now propose are therefore well-within the scope of NOT-AG-18-039.